Dravet Spectrum disorders resulting from SCN1A loss-of-function mutations include febrile seizures, generalized epilepsy with febrile seizure plus (GEFS+), and Dravet syndrome (severe myoclonic epilepsy of infancy or SMEI), in order of increasing severity. In the most severe cases, progressive developmental and behavioral impairments manifest along with the recurrent and varied seizure episodes that advance to include multiple seizure types by age 2. In many patients, seizures are resistant to currently available antiepileptic drugs. Thus, there is a significant and urgent need for the development of novel approaches to therapy. SCN1 channel function in inhibition is functionally opposed by the related SCN8 channel. Thus, a validated and logical strategy for rebalancing the deficit of inhibitory input caused by SCN1A loss-of-function mutation is to specifically reduce SCN8-mediated excitation. VGS channel alpha subunits undergo several alternative splicing events which regulate the inhibitory and excitatory balance of sodium currents in the CNS. SCN8A subunits are naturally alternatively spliced at two specific sites of interest which control channe function or kinetics. A novel strategy to reduce SCN8A- mediated excitation and seizures associated with SCN1A loss-of-function mutations as a treatment for DS is to direct splicing at each of these sites by developing compounds called splice modulating oligonucleotides (SMOs). SMOs are a class of synthetic RNA based compounds that sterically block or weaken interactions between elements of the splice machinery and the pre-mRNA. SMOs are ideal but under-developed drug candidates as they bind to their targets with exceptional potency, specificity, and negligible off-target effects. SMOs targeting SCN8A splicing will designed in silico and refined for potency and specificity in vivo (Aim 1) leading to an SMO drug candidate for each splice site. Each SMO candidate will be characterized by dose-response in normal mice at P10-42 days, and SMO dose-effect on flurothyl-induced seizure threshold evaluated in normal mice (Aim 2). Finally, SMOs will be evaluated as therapeutics in SNN1A R1648H mutant mice (Aim 3), for effects on longevity, motor function (ataxia, tremor) and flurothyl-induced seizure susceptibility. Safety and efficacy of SMO treatment will further be assessed for both positive and adverse effects on behavior in adult heterozygous SCN1A R1648H mice, which have a normal lifespan. The strategy of specifically reducing only the Na+ channel (SCN8A) that counterbalances SCN1A input should be more efficacious and be much less likely to cause unwanted effects than using sodium channel blockers which antagonize multiple VGS channels. The ultimate goal is to develop these SMOs as potential therapeutic for the treatment of Dravet Syndrome and related disorders in patients resistant to currently available pharmacotherapies.